Friday, March 22, 2024

Diamyd Update Part 2: JDRF Flexibilty In Funding and Diamyd In More People

My previous blog posting:
https://cureresearch4type1diabetes.blogspot.com/2023/12/diamyd-update.html
described the main line of DIAGNODE clinical trials designed to get Diamyd FDA approval for people in their honeymoon phase.  You should read that posting for a lot of background material.  In this blog, I'm going to cover two additional clinical trials aimed at expanding the people who can use this treatment and some interesting details about how JDRF is funding this research.

DIAGNODE Expansion Trials

These two trials are using the same DIAGNODE technique (injecting Diamyd into the lymph nodes of people with the HLA DR3-DQ2 gene).  The first is aimed at people who are at-risk of T1D, rather than the honeymooners, which is what previous trials focused on.  The second is aimed at people with LADA, rather than people with the more classic T1D onset, which is (again) what previous trials focused on.

DiaPrecise (Diamyd For At-Risk)

 

This is a small (16 people), trial where half the people get 2 Diamyd injections and the other half get 3, so there is no control group.  Everyone in the study has two autoantibodies, but has not yet been diagnosed with T1D.  Using Trialnet terminology they are in stage 1.

This study is ongoing now and is expected to finish in 2025.

GADinLADA (Diamyd For LADA)


This is another small (14 person), phase-II trial done on people with LADA (an autoimmune form of diabetes diagnosed in older people).  People got three injections of Diamyd, one month apart, into lymph nodes.
 
It was successful in the sense that there were no serious side effects, and it is clear that they can do a larger, randomized, blinded study in the future if they wish.  However, I can't evaluate if Diamyd actually helped these people.  They have published C-peptide numbers, which show that the people who got the treatment lost some of their ability to generate C-peptide.  This is not good, but I don't know what happens to people who are not treated, so I cannot tell if the Diamyd helped them or not. 

Journal Article: https://dom-pubs.onlinelibrary.wiley.com/doi/pdf/10.1111/dom.15239

Money: JDRF, but not T1D Fund

Diamyd (the company) has gotten some money from JDRF through their Industry Partnership Program, and that money is contingent on Diamyd (the treatment) meeting certain successful results.  For me, this is a very interesting development and warrants some discussion.

In the past JDRF operated like most other medical research charities (and the US government) and gave grants to researchers.  The researchers would propose research and if JDRF liked it, they would give the researchers the money to do it.  This is the way most non-profits fund most of their research even to this day.  

However, in 2016 some people active in JDRF became frustrated by the gap between academic research (funded by grants) and commercial research which, for small companies, was funded by venture capital and for large companies, by corporate capital.  So they created The T1D Fund: https://t1dfund.org (especially read the "about" tab).

This fund uses money seeded into it by JDRF and from other sources (mostly wealth investors) to fund commercial medical development work aimed at T1D.  It operates as a venture capital firm.  It makes investments in companies doing work in the T1D space.  As investors they are (generally) part owners of the companies they invest in, and if those companies are successful, they will profit from the success.  Those profits will then be rolled into new investments.

A complete description of how venture capital works (and therefore how the T1D Fund works) is well beyond what I can do in a blog post.  I can't even (quickly) find a good on-line summary that someone else has written!

So as of 2016, there were two separate funding methods for getting T1D products to market: 

  • JDRF, traditional grant-based early research focused.
  • The T1DFund, venture capital-based and early product development focused.

But now (finally) to the Diamyd point: the funding that Diamyd received is not exactly either of these two funding methods.  It is in between.  The money is coming from JDRF but has some very business like conditions, as described in the bullet point items below.  (These items are taken from a Diamyd press release.)

  • Payments from JDRF are earned when Diamyd Medical completes various milestones in the DIAGNODE-3 study, with these milestones spanning the years 2023 - 2027. 
  • JDRF can also use its global type 1 diabetes network to raise awareness of the study, which may contribute to patient recruitment, and also provide advisement as Diamyd Medical prepares for a potential commercial approval. 
  • If Diamyd Medical in the future gets Diamyd® commercially approved and the sale of the drug becomes a commercial success, JDRF will receive a limited royalty on the revenue, if within the framework of the partnership agreement. 

These are all very business like terms; similar to how one company funds another.  I discuss the details more below, but the summary point is that JDRF is expanding the kinds of funding it can give which adds flexibility to all future investments.  For me, this is a good thing because you never know which kind of investment will benefit a new line of research the most.

Why is all this important?

Most importantly, it means that JDRF will share in the monetary success of Diamyd, if there is any.  This is very different than traditional research grant work, and it addresses a recent frustration.  I know some people were frustrated because JDRF has put money into the academic research with led to the development of Teplizumab, but had not gotten any money out when Teplizumab became a commercial product or even when the company was bought out (for $3 billion US dollars!)  This is perfectly normal in academic grant making, which is traditionally what medical research non-profits have done, but it can leave a bad taste in a donor's mouth.  The Diamyd funding model avoids this.

Also important: Diamyd only gets money when they meet certain milestones.  This is not speculative research grant money;  this is payment on success, motivational money.  It is very common in the world of corporate financing, but I've never before seen it in the world of research grant making.

In another way, I view this as JDRF having more flexibility in funding cures than academic research projects, but not yet self-funding commercial projects. 

Press release: https://www.diamyd.com/docs/pressClips.aspx?ClipID=4676370

Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My kid has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

 

Friday, March 8, 2024

Levicure's Combination Therapy

Levicure is a startup which is currently raising money to fund a phase-II trial for a combination therapy designed to prevent or delay T1D if given during the honeymoon period.  This blog posting is reporting on the results of their retrospective phase-I clinical trial.  That trial has already been completed and is motivating them to move forward with a larger phase-II trial. 

The combination therapy used three medicines: GABA, Sitagliptin or Saxagliptin (which are dipeptidyl peptidase-4 inhibitors), and Omeprazole (a proton pump inhibitor).  All three of these drugs are available now, and all have some evidence that they will help people with diabetes.  They have all been tested (in some cases in combination with other medicines and each other).  However, I think this is the first clinical trial that has reported on these three together.

The Study

This was a retrospective study, where the researchers reviewed the medical records of people who had been treated with the three drugs.  The people were given the three drugs because their doctors thought it was the right treatment for them, not because they were enrolled in a trial.  There is no randomization process and no control group.  The trial size is determined by how many people got all three treatments in the time period the researchers looked at.

The researchers ended up with 19 people. Ten of them had received the three drugs during the first year after diagnosis (their honeymoon period).  Nine more had received the drugs after that, so they had established T1D.  The two groups were analyzed separately.

Results

The group (ten people) that started therapy during their honeymoon phase, called "early therapy" below had a statistically significant rise in C-Peptide production.  The average went from just over 200 pmol/L to just under 500.  Since the average for a person without T1D is at least 365, this is an important difference, as the change is from an abnormal result to a normal one.  (All of these are fasting numbers.) 


The group (nine people) that started the treatment more than a year after the onset of T1D did not show an improvement in their C-Peptide number, and none of them was able to stop injecting insulin.  They did show improvements in treating T1D (using less insulin, having better A1c numbers, etc.)

Company: https://www.levicure.com/
History: https://healthtransformer.co/levicure-is-developing-a-breakthrough-triple-therapy-for-type-1-diabetes-b6c521e6b2c5
Clinical Trial Report: https://www.frontiersin.org/articles/10.3389/fendo.2023.1171886/full
Animal Testing: https://www.frontiersin.org/articles/10.3389/fendo.2022.1028114/full

Discussion

LADA vs. Classic T1D

Discussion of this study needs to start out with the question: Is it a LADA study, or is it a classic T1D study, and are they different?  

The successful (early treatment) part of this study enrolled people between the ages of 17 and 58 (average age was 31 and standard deviation was 13 years), so about half of these people had LADA rather than classic type 1 diabetes.  LADA stands for Latent Autoimmune Diabetes in Adults; you can think of it as classic T1D, but diagnosed in adults.  A common cut off is 30 years old.  People under that age are said to have classic T1D and after that age, LADA.  LADA has a honeymoon, just as T1D does, but it is not the same.  It is well known to be longer and stronger.  This makes it easier for drugs that delay/extend the honeymoon to work better on LADA than on T1D.  Therefore, we don't know if the good results seen here for many people with LADA are going to be as good in people with classic T1D.

Prospective vs. Retrospective Studies

I usually report on prospective studies, which are inherently more reliable than retrospective studies, and this study was retrospective.  In this case, these researchers are already raising money for another study and that new study will be prospective, so it will provide a better signal as to the success of the treatment.  In the meantime, there is nothing to do but wait, and hope they can raise the money quickly.

Similar Studies With Semaglutide

The obvious clinical trial to compare this to is the Semaglutide study which I blogged on here:
https://cureresearch4type1diabetes.blogspot.com/2023/09/strong-results-from-pilot-study-of.html
That study was in many ways very similar, both in study design and result.  They were both retrospective studies based on clinical practice, and they both had many people off insulin for a year in the honeymoon phase.

Interestingly, Semaglutide has a similar mechanism of effect to Sitagliptin or Saxagliptin.  They all end up impacting glucagon-like peptide-1 (GLP-1).  However, Semaglutide is an injected drug while Sitagliptin and Saxagliptin (tested here) are pills. 

Availability Now

The three drugs tested here are all commonly available.  GABA is a dietary supplement, Omeprazole is sold both over the counter and by prescription.  Only the second component: Sitagliptin or Saxagliptin is a prescription drug and both have been approved for use since the late 2000s.  They each have a generally good safety profile.  If you want to have an "off label" discussion with your doctor, the exact dosing information is in the clinical trial report (link above).

 

Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My kid has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

 

Monday, January 29, 2024

Results from a Phase-IIΔ Trial of Pleconaril and Ribavirin

This clinical trial represents an attack on T1D slightly different than anything I've blogged on before.

Pleconaril and Ribavirin are both antiviral drugs.  The idea here is that viruses either cause T1D or contribute to it, and that attacking viruses during the early honeymoon period will do something good.   Maybe delay the onset, extend the honeymoon, or even allow the long term survival of more beta cells to lower long term complications of T1D.  

I want to stress that this "virus causes T1D" hypothesis is just that: a hypothesis.  It is held by some researchers, but is not the consensus cause of T1D.  However, these researchers are moving forward assuming it is true, and therefore testing a prevention technique that is likely to work if it is true.  They had previously found low grade enteroviral infection in the pancreas of people recently diagnosed with T1D, and that motivated them to run this study.  

The study participants were between 6 and 15 years old and within 3 weeks of diagnosis.  These were early honeymooners.  The drug combination was in liquid form and drunk daily for six months, and then the people were followed for an additional six months, which is reported here.  Although they reported results in October, the study will continue for two more years and so we should get more results in the future.

The key finding was "During the 12-month study period, the relative decrease in C-peptide was 11% in the Pleconaril and Ribavirin group and 24% in the placebo group" (paraphrased).  So both groups dropped, but the treated group dropped much less.  See here for more discussion of why these sorts of results do not excite me.

This study was supported by JDRF, INNODIA and others.

 

Discussion

The idea that a virus causes T1D, or triggers it, or make it worse, is widely held.  Many parents remember that their kids were sick just before or as part of their T1D diagnosis.  However, the causality part has not been proven.  Viruses may cause T1D, or they might trigger it (i.e. the person was going to get T1D anyway, and the virus just caused it to manifest now rather than next month), or it may be that early T1D symptoms are similar enough to the flu so that people get them mixed up, or it might be that after a diagnosis of T1D, parents suddenly connect it to the last illness the child had.

On the other hand, Coxsackie B viruses (a type of enterovirus) have been associated with T1D in previous population studies, and enteroviruses are known to target pancreatic islets.  There is another clinical trial which attempts to use a Coxsackie B vaccine to lower the rate of T1D, and a third using flu vaccine on people in the honeymoon phase.  So the causal part is certainly possible. 

About these anti-virals specifically, I think it is important to note that Pleconaril was never approved for use by the FDA because of side effects.  It was evaluated in the early 2000s.  Ribavirin is approved, but use in T1D would be "off label" and its label includes two black box warnings.

To me, these results seem similar to the Teplizumab in honeymooners results, although with the obvious caveat that this result is in a 100 person phase-IIΔ study, and the Teplizumab study was a 300 person phase-III study.  The Teplizumab honeymoon trial reported a difference of 0.13 pmol/ml while this study reported 0.16 pmol/ml.

But also, this study only shows preservation of beta cells (and not even complete preservation), and I usually only get excited about beta cell regrowth in the honeymoon phase.

Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My kid has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.